Agents of the tribe Ehrlichiae cause a variety of tick-borne diseases in both humans and animals. Many of these agents persist in the host thus acting as potential reservoirs for further spread of disease. Anaplasma marginale is closely related genetically (16S rRNA) with E. phagocytophila, the causative agent of human granulocytic ehrlichiosis (HGE). Indeed, both organisms express antigenically variant outer membrane proteins, major surface protein-2 (MSP-2) that share significant amino acid sequence conservation characterized by highly conserved N and C terminal regions and a central, hydrophilic, hypervariable region. Levels of rickettsemia during persistent anaplasmosis are approximately two orders of magnitude less than rickettsemia levels during acute infection and do not result in clinical disease. We hypothesize that the control of rickettsemia to levels significantly below those observed during acute clinical anaplasmosis is due to a memory CD4+ Th-cell response to conserved epitopes on MSP-2 that enhance variant specific B cell responses directed against the hypervariable region. The results of this research will provide insight into means of developing outer membrane protein-based vaccines against A. marginale and other ehrlichial organisms that cause disease in animals and humans, especially the closely related agent of HGE, E. phagocytophila